Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2019 Publisher: LEO Pharma Limited, Auckland, New Zealand, Toll Free No. 0800 497 456
Pharmacotherapeutic group: Corticosteroids, potent (group III)
ATC code: D07AC14
After topical application, ADVANTAN suppresses inflammatory and allergic skin reactions as well as reactions associated with hyperproliferation, leading to regression of the objective symptoms (erythema, oedema, infiltration, lichenification) and the subjective complaints (itching, burning, pain).
On application of methylprednisolone aceponate in topically effective dosage, the systemic effect is minimal in both man and animals. After large-area treatment of patients with skin disorders, levels of plasma cortisol remain within the normal range, circadian cortisol rhythm is maintained, and no reduction of cortisol has been ascertained in 24-hour urine.
As for all other glucocorticoids, the mechanism of action of methylprednisolone aceponate is not completely understood. It is known that methylprednisolone aceponate itself binds to the intracellular glucocorticoid receptor and this is especially true of the principal metabolite 6α-methyl-prednisolone-17-propionate, which is formed after cleavage in the skin. The steroid receptor complex binds to certain regions of DNA, thereby triggering a series of biological effects.
The understanding of the mechanism of the anti-inflammatory action is more precise. Binding of the steroid receptor complex results in induction of macrocortin synthesis. Macrocortin inhibits the release of arachidonic acid and thus the formation of inflammation mediators such as prostaglandins and leukotrienes.
The immunosuppressive action of glucocorticoids can be explained by inhibition of cytokine synthesis, and an antimitotic effect, which so far is not well understood.
Inhibition of the synthesis of vasodilating prostaglandins or potentiation of the vasoconstrictive effect of epinephrine finally results in the vasoconstrictive activity of glucocorticoids.
The respective bases are of major importance to the therapeutic effect of the ADVANTAN formulations.
As a low-fat formulation with a high water content, ADVANTAN Cream is particularly suitable for acute and subacute weeping stages of eczema, for very greasy skin and for use on exposed or hairy parts of the body.
Skin conditions which are neither weeping nor very dry require a base with balanced proportions of fat and water. ADVANTAN Ointment is suitable for dry, fissured, scaly or hyperkeratinised skin areas. It should not be used in areas such as axilla, groin or skin folds. ADVANTAN Ointment makes the skin slightly greasy without retaining warmth and fluid. Of the three formulations, ADVANTAN Ointment has the widest field of use.
Methylprednisolone aceponate (MPA) becomes available in the skin from all formulations (cream, ointment). The concentration in the stratum corneum and living skin decreases from outside to inside.
Methylprednisolone aceponate is hydrolysed in the epidermis and dermis to the main metabolite 6α-methylprednisolone-17-propionate, which binds more firmly to the corticoid receptor – an indication of “bioactivation” in the skin.
The degree of percutaneous absorption depends on the state of the skin, the formulation and the conditions of application (open/occlusion). Studies in juvenile and adult patients with neurodermatitis and psoriasis have shown that the percutaneous absorption on open application was only slightly (≤2.5%) greater than the percutaneous absorption in volunteers with normal skin (0.5-1.5%).
When the horny layer is removed before the application, the corticoid levels in the skin are about three times higher than after application to intact skin.
After reaching the systemic circulation, the primary hydrolysis product of MPA, 6αmethylprednisolone-17-propionate, is quickly conjugated with glucuronic acid and inactivated as a result.
The metabolites of MPA (main metabolite: 6α -methylprednisolone-17-propionate-21-glucuronide) are eliminated primarily via the kidneys with a half-life of about 16 hours. Following intravenous administration, excretion of the 14C-labeled substances with the urine and faeces was complete within 7 days. No accumulation of substance or metabolites takes place in the body.
In systemic tolerance studies following repeated subcutaneous and dermal administration, MPA showed the action profile of a typical glucocorticoid. It can be concluded from these results that following therapeutic use of ADVANTAN no side-effects other than those typical of glucocorticoids are to be expected, even under extreme conditions such as application over a large surface area and/or occlusion.
Specific tumourigenicity studies using MPA have not been carried out. Knowledge concerning the structure, the pharmacological effect mechanism and the results from systemic tolerance studies with long-term administration do not indicate any increase in the risk of tumour occurrence. As systemically effective immunosuppressive exposure is not reached with dermal application of ADVANTAN under the recommended conditions of use, no influence on the occurrence of tumours is to be expected.
Neither in vitro investigations for detection of gene mutations on bacteria and mammalian cells nor in vitro and in vivo investigations for detection of chromosome and gene mutations gave any indication of a genotoxic potential of MPA.
Animal studies with MPA have shown embryolethal defects in rats dosed subcutaneously during the period of organogenesis at doses greater than 1 mg/kg/day and in rabbits following dermal application at doses greater than 0.25 mg/kg/day. No teratogenic effects were observed in rabbits, but in rats the incidences of ventricular septal defects and of cleft palate were increased at subcutaneous doses greater than 1 and 10 mg/kg/day. Similar embryolethal and teratogenic effects have been found with other corticosteroids and while not considered relevant to humans, particular care should be taken when prescribing ADVANTAN during pregnancy.
In investigations into the local tolerance of MPA and ADVANTAN formulations on the skin and the mucosa, no findings other than the topical side-effects known for glucocorticoids were recorded. MPA showed no sensitising potential on the skin of the guinea-pig.
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